Fumarase affects the deoxyribonucleic acid damage response by protecting the mitochondrial desulfurase Nfs1p from modification and inactivation

Joyce Yip; Suqing Wang; Jasper Tan; Teck Kwang Lim; Qingsong Lin; Zhang Yu; Ofri Karmon; Ophry Pines; Norbert Lehming

doi:10.1016/j.isci.2021.103354

Fumarase affects the deoxyribonucleic acid damage response by protecting the mitochondrial desulfurase Nfs1p from modification and inactivation

iScience. 2021 Oct 26;24(11):103354. doi: 10.1016/j.isci.2021.103354. eCollection 2021 Nov 19.

Authors

Joyce Yip¹, Suqing Wang¹, Jasper Tan¹, Teck Kwang Lim², Qingsong Lin², Zhang Yu³, Ofri Karmon³, Ophry Pines³, Norbert Lehming¹

Affiliations

¹ Department of Microbiology and Immunology, Cancer Programme at NUSMED, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Block MD4, Level 5, Singapore 117545, Singapore.
² Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, Singapore.
³ Department of Microbiology and Molecular Genetics, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Israel; CREATE-NUS-HUJ Program and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Abstract

The Krebs cycle enzyme fumarase, which has been identified as a tumor suppressor, is involved in the deoxyribonucleic acid (DNA) damage response (DDR) in human, yeast, and bacterial cells. We have found that the overexpression of the cysteine desulfurase Nfs1p restores DNA repair in fumarase-deficient yeast cells. Nfs1p accumulates inactivating post-translational modifications in yeast cells lacking fumarase under conditions of DNA damage. Our model is that in addition to metabolic signaling of the DDR in the nucleus, fumarase affects the DDR by protecting the desulfurase Nfs1p in mitochondria from modification and inactivation. Fumarase performs this protection by directly binding to Nfs1p in mitochondria and enabling, the maintenance, via metabolism, of a non-oxidizing environment in mitochondria. Nfs1p is required for the formation of Fe-S clusters, which are essential cofactors for DNA repair enzymes. Thus, we propose that the overexpression of Nfs1p overcomes the lack of fumarase by enhancing the activity of DNA repair enzymes.

Keywords: Biochemistry; Biological sciences; Molecular biology.